Patent GB-1007583-A (GB)
Title: Improvements in or relating to benz[e,d]indole derivatives and the manufacture thereof
IPC: A61K8/49
Filed: 1962-07-09
Abstract: The invention comprises compounds of the general formula <FORM:1007583/C2/1> wherein R is hydrogen or alkyl of from 1 to 8 carbon atoms, R1 is hydrogen, alkyl of from 1 to 4 carbon atoms, phenyl, hydroxyphenyl, alkoxyephenyl wherein alkoxy is of from 1 to 4 carbon atoms, or halophenyl, R2 is hydrogen, alkanoyl of from 1 to 4 carbon atoms, benzyl or halobenzyl which can be substituted with alkyl or alkoxy of from 1 to 4 carbon atoms, or alkyl of from 1 to 4 carbon atoms, R3 is hydroxy, benzyloxy, alkyl of from 1 to 4 carbon atoms, halogen, or alkoxy of from 1 to 4 carbon atoms, and n is zero, 1 or 2.  The compounds wherein R is H may be prepared by subjecting a compound of the general formula <FORM:1007583/C2/2> to cyclization with aluminium chloride, R1, R3 and n being as defined above, R4 being alkanoyl of from 1 to 4 carbon atoms, benzyl or halobenzyl which can be substituted with alkyl or alkoxy of from 1 to 4 carbon atoms, or alkyl of from 1 to 4 carbon atoms, The compounds of Formula III above may be prepared by dehydrating a compound of the general formula <FORM:1007583/C2/3> with the isopropenyl ester of an alkionic acid of from 1 to 4 carbon atoms, R1, R2, R3 and n being as defined above.  The compounds of Formula III above wherein R4 is alkanoyl may also be prepared by reacting the corresponding compound in which R4 is hydrogen with an isopropenyl ester of the above type.  The compounds of formula 2 above may be prepared: (a) when R1 is other than hydrogen by condensing the corresponding 3-unsubstituted indole with maleic acid or maleic anhydride; when maleic anhydride is used it is sometimes unnecessary to go through the succinic acid stage but usually the anhydride is hydrolysed to the acid of Formula II; (b) when R1 is hydrogen a 3-indole-carboxaldehyde is condensed with ethyl cyanoacetate or diethyl malonate, reacting the condensed product with potassium cyanide in ethanol, and hydrolysing the resulting cyano derivative with aqueous potassium hydroxide.  The 3-indole-carboxaldehydes can be prepared by reacting a 3-unsubstituted indole with dimethylformamide. When compounds of formula I in which R3 is hydroxy are desired, the corresponding benzyloxy-substituted compounds of formula I are prepared and are then subjected to hydrogenolysis. If the starting indole compound contains an N-hydrogen (R2=H) the reaction with an isopropenyl ester will acylate the nitrogen atom; this acyl group may be removed from the compound of Formula I by hydrolysis or may be retained in the molecule during further processing steps and removed by hydrolysis when and if desired. The acids of Formula I may be esterified by conventional methods, optionally via the acid chlorides, and the resultant esters may be purified and then hydrolysed to the acids, resulting in upgrading of the acids.  The compounds of the invention wherein R is H may be esterified in accordance with U.S.A Specification 2,220,521, to form betathiocyanoethyl esters.  The 5-oxo group of the compounds of Formula I may be reacted with carbonyl binding agents such as semicarboxide, thiosemicarboxide and 2,4-dinitrophenylhydrazine. Many suitable values of R, R1, R2, R3 and R4 are specified.  Examples are given. In examples: (5) 2-methylindole is reacted with methyl iodide and dimethyl-formamide to give 1,2-dimethylindole; (6) p-methoxyacetophenone is reacted with phenyl-hydrazine to give 2-(p - anisyl) - indole; (7) p - methoxy - acetophenone is reacted with 1-methyl-1-phenyl-hydrazine to give 1-methyl-2-(p-anisyl)-indole; (8) 3,4,5 - trimethoxyacetophenone is prepared by reacting 3,4,5-trimethoxybenzoyl chloride with cadmium chloride and methyl-magnesium iodide and is then reacted with phenylhydrazine to give 2-(3,4,5-trimethoxyphenyl) - indole; (9) 2 - (p - anisyl) - indole is treated with pyridine to give 2-(p-hydroxybenzyl)-indole; (10 p-fluoroacetophenone is reacted with phenylhydrazine to give 2-(p-fluorophenyl)-indole.